Involvement of the ATR- and ATM-dependent checkpoint responses in cell cycle arrest evoked by pierisin-1

Molecular Cancer Research : MCR
Bunsyo ShiotaniKeiji Wakabayashi

Abstract

Pierisin-1 identified from the cabbage butterfly, Pieris rapae, is a novel mono-ADP-ribosylating toxin that transfers the ADP-ribose moiety of NAD at N(2) of dG in DNA. Resulting mono-ADP-ribosylated DNA adducts cause mutations and the induction of apoptosis. However, little is known about checkpoint responses elicited in mammalian cells by the formation of such bulky DNA adducts. In the present study, it was shown that DNA polymerases were blocked at the specific site of mono-ADP-ribosylated dG, which might lead to the replication stress. Pierisin-1 treatment of HeLa cells was found to induce an intra-S-phase arrest through both ataxia telangiectasia mutated (ATM) and Rad3-related (ATR) and ATM pathways, and ATR pathway also contributes to a G(2)-M-phase delay. In the colony survival assays, Rad17(-/-) DT40 cells showed greater sensitivity to pierisin-1-induced cytotoxicity than wild-type and ATM(-/-) DT40 cells, possibly due to defects of checkpoint responses, such as the Chk1 activation. Furthermore, apoptotic 50-kb DNA fragmentation was observed in the HeLa cells, which was well correlated with occurrence of phosphorylation of Chk2. These results thus suggest that pierisin-1 treatment primarily activates ATR pathway and eve...Continue Reading

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Citations

Jun 10, 2008·Nature Cell Biology·Melanie WinterThomas G Hofmann
Apr 21, 2009·Nature Cell Biology·Chunyan TianFuchu He
Jan 13, 2010·The Journal of Biological Chemistry·Roberto R RosatoSteven Grant
Mar 1, 2012·The Plant Cell·Teresa B FitzpatrickAlisdair R Fernie
Sep 12, 2021·Nucleic Acids Research·Callum Tromans-CoiaIvan Ahel

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